Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 69

Abstract

Demyelination and Schwann cell (SC) proliferation are hallmarks of hypertrophic demyelinating neuropathies, of which Charcot‐Marie‐Tooth type 1 A (CMT1A) neuropathy is the typical example. In CMT1A, an altered dosage of the PMP22 gene determines a defect of myelination and an abnormal SC phenotype, characterized by hyperplasia and abnormal differentiation. The Epidermal Growth Factor (EGF) family of proteins, including EGF and neuregulins, and their receptors, namely EGFr and the erbB family, control growth and development of SC. Their expression in mature SC is down‐regulated but, during Wallerian degeneration or chemical myelinolysis, these receptors are transiently over‐expressed, suggesting a potential autocrine mechanism. On the other hand, neuregulin 1 inhibits SC myelination and induces demyelination and SC dedifferentiation and proliferation. These effects might play a role in the pathogenesis of hypertrophic demyelinating neuropathies. We have therefore immunolocalized EGF, EGFr and the erbB receptors (erbB 2, 3 and 4) in sural nerve biopsies from patients with CMT1A as compared to chronic inflammatory demyelinating neuropathy (CIDP) nerve biopsies and to normal nerves, in order to evaluate if the expression of these molecules is up‐ or down‐regulated in these disorders. Among CMT1A nerves, immunoreactivity for EGF, EGFr, erbB2 and erbB3 was moderately to markedly increased in SC, particularly in onion bulbs, in most cases, while a mild to moderate expression of erbB 4 in SC cytoplasm was observed in a few cases. On the other hand in CIDP, which shares with CMT1A histopathological features such as de‐remyelination and SC hyperplasia, only the expression of erbB 3 was up‐regulated in a minority of cases. Since in SC the functional neuregulin receptor is a heterodimer, composed by erbB2 and erbB3, the parallel up‐regulation of these two molecules in CMT1A may bear a functional significance. This would be confirmed if an overexpression of neuregulins could be demonstrated, along with our finding of an increased expression of EGF and its receptor. In conclusion, it can be hypothesized that, in CMT1A, a persistent activation of neuregulin signaling pathways not only is indicative of SC dedifferentiation but also may contribute to demyelination and onion bulb formation or maintenance.